A STAT3 protein complex required for mitochondrial mRNA stability and cancer

C. Dilanka Fernando; W. Samantha N. Jayasekara; Chaitanya Inampudi; Maija R.J. Kohonen-Corish; Wendy A. Cooper; Traude H. Beilharz; Tracy M. Josephs; Daniel J. Garama; Daniel J. Gough

doi:10.1016/j.celrep.2023.113033

A STAT3 protein complex required for mitochondrial mRNA stability and cancer

C. Dilanka Fernando, W. Samantha N. Jayasekara, Chaitanya Inampudi, Maija R.J. Kohonen-Corish, Wendy A. Cooper, Traude H. Beilharz, Tracy M. Josephs, Daniel J. Garama, Daniel J. Gough

Research output: Contribution to journal › Article › Research › peer-review

13 Citations (Scopus)

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.

Original language	English
Article number	113033
Number of pages	14
Journal	Cell Reports
Volume	42
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2023.113033
Publication status	Published - 26 Sept 2023

Keywords

CP: Cancer
CP: Molecular biology
LRPPRC
lung adenocarcinoma
mitochondria
mRNA stability
SLIRP
STAT3

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2023.113033Licence: CC BY-NC-ND

Cite this

@article{09ee923169ab46399555565e0834865b,

title = "A STAT3 protein complex required for mitochondrial mRNA stability and cancer",

abstract = "Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.",

keywords = "CP: Cancer, CP: Molecular biology, LRPPRC, lung adenocarcinoma, mitochondria, mRNA stability, SLIRP, STAT3",

author = "Fernando, {C. Dilanka} and Jayasekara, {W. Samantha N.} and Chaitanya Inampudi and Kohonen-Corish, {Maija R.J.} and Cooper, {Wendy A.} and Beilharz, {Traude H.} and Josephs, {Tracy M.} and Garama, {Daniel J.} and Gough, {Daniel J.}",

note = "Funding Information: We thank the MHTP flow cytometry core, the Monash Medical Center Animal Facility, the Monash Micro Imaging Platform, Micromon, and the Bio21 Proteomics Facility for their expertise; M. Pagano, D. Levy, and J. StJohn for gifts of reagents; J. Balic and P. Hertzog for helpful discussions and editing; and G. Ballerin for image analysis support. This work is supported by the Operational Infrastructure Support Program by the Victorian Government of Australia . D.J. Gough is supported by a fellowship from the Victorian Cancer Agency ( MCRF19033 ) and a grant from the Cancer Council Victoria ( GNT1145028 ). D.J. Garama is supported by funding from the CASS Foundation . C.D.F. was supported by a Monash Research Training Scholarship . T.M.J. is an NHMRC Emerging Leader Fellow ( 2008341 ). Images were created in BioRender. Funding Information: We thank the MHTP flow cytometry core, the Monash Medical Center Animal Facility, the Monash Micro Imaging Platform, Micromon, and the Bio21 Proteomics Facility for their expertise; M. Pagano, D. Levy, and J. StJohn for gifts of reagents; J. Balic and P. Hertzog for helpful discussions and editing; and G. Ballerin for image analysis support. This work is supported by the Operational Infrastructure Support Program by the Victorian Government of Australia. D.J. Gough is supported by a fellowship from the Victorian Cancer Agency (MCRF19033) and a grant from the Cancer Council Victoria (GNT1145028). D.J. Garama is supported by funding from the CASS Foundation. C.D.F. was supported by a Monash Research Training Scholarship. T.M.J. is an NHMRC Emerging Leader Fellow (2008341). Images were created in BioRender. Study conception and design, D.J. Gough and D.J. Garama; experiments and data analysis, all authors; manuscript writing and editing, all authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = sep,

day = "26",

doi = "10.1016/j.celrep.2023.113033",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "9",

}

TY - JOUR

T1 - A STAT3 protein complex required for mitochondrial mRNA stability and cancer

AU - Fernando, C. Dilanka

AU - Jayasekara, W. Samantha N.

AU - Inampudi, Chaitanya

AU - Kohonen-Corish, Maija R.J.

AU - Cooper, Wendy A.

AU - Beilharz, Traude H.

AU - Josephs, Tracy M.

AU - Garama, Daniel J.

AU - Gough, Daniel J.

N1 - Funding Information: We thank the MHTP flow cytometry core, the Monash Medical Center Animal Facility, the Monash Micro Imaging Platform, Micromon, and the Bio21 Proteomics Facility for their expertise; M. Pagano, D. Levy, and J. StJohn for gifts of reagents; J. Balic and P. Hertzog for helpful discussions and editing; and G. Ballerin for image analysis support. This work is supported by the Operational Infrastructure Support Program by the Victorian Government of Australia . D.J. Gough is supported by a fellowship from the Victorian Cancer Agency ( MCRF19033 ) and a grant from the Cancer Council Victoria ( GNT1145028 ). D.J. Garama is supported by funding from the CASS Foundation . C.D.F. was supported by a Monash Research Training Scholarship . T.M.J. is an NHMRC Emerging Leader Fellow ( 2008341 ). Images were created in BioRender. Funding Information: We thank the MHTP flow cytometry core, the Monash Medical Center Animal Facility, the Monash Micro Imaging Platform, Micromon, and the Bio21 Proteomics Facility for their expertise; M. Pagano, D. Levy, and J. StJohn for gifts of reagents; J. Balic and P. Hertzog for helpful discussions and editing; and G. Ballerin for image analysis support. This work is supported by the Operational Infrastructure Support Program by the Victorian Government of Australia. D.J. Gough is supported by a fellowship from the Victorian Cancer Agency (MCRF19033) and a grant from the Cancer Council Victoria (GNT1145028). D.J. Garama is supported by funding from the CASS Foundation. C.D.F. was supported by a Monash Research Training Scholarship. T.M.J. is an NHMRC Emerging Leader Fellow (2008341). Images were created in BioRender. Study conception and design, D.J. Gough and D.J. Garama; experiments and data analysis, all authors; manuscript writing and editing, all authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2023 The Author(s)

PY - 2023/9/26

Y1 - 2023/9/26

N2 - Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.

AB - Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.

KW - CP: Cancer

KW - CP: Molecular biology

KW - LRPPRC

KW - lung adenocarcinoma

KW - mitochondria

KW - mRNA stability

KW - SLIRP

KW - STAT3

UR - http://www.scopus.com/inward/record.url?scp=85170673035&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.113033

DO - 10.1016/j.celrep.2023.113033

M3 - Article

C2 - 37703176

AN - SCOPUS:85170673035

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 113033

ER -

A STAT3 protein complex required for mitochondrial mRNA stability and cancer

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

A personalised pharmacogenomic approach to inform autosomal dominant hypocalcaemia treatment

ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery

Developing new therapies to improve Small Cell Lung Cancer patient outcomes

FlowCore (FLOW)

Monash Genomics & Bioinformatics Platform (MGBP) Genomics Node

Monash Micro Imaging (MMI)

Cite this

A STAT3 protein complex required for mitochondrial mRNA stability and cancer

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

A personalised pharmacogenomic approach to inform autosomal dominant hypocalcaemia treatment

ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery

Developing new therapies to improve Small Cell Lung Cancer patient outcomes

Equipment

FlowCore (FLOW)

Monash Genomics & Bioinformatics Platform (MGBP) Genomics Node

Monash Micro Imaging (MMI)

Cite this